ABSTRACT Tuberculosis (TB) remains a public health problem worldwide, but yet effective vaccine and short treatment regimens are missing due in part to the lack of a complete understanding of the host immune response and its dynamic during treatment. TB patients are at 13 times higher risk of developing another episode of TB than the general population. Previous studies have shown that the major TB drugs, isoniazid, rifampin, ethambutol and pyrazinamide, create a profound long-standing alteration of gut microbiota that may play a negative role on host immune response. This may thereby impact treatment efficacy and duration, and furthermore expose patients to future TB infections. In fact, this resulting dysbiosis from TB treatment correlates well with the magnitude of TB bacterial clearance during therapy, which decreases significantly as the treatment progresses. However, at present it is not known what are the consequences of the dysbiosis resulting from a treatment taken by many millions of patients worldwide. This project will investigate the direct link between mucosal microbial profiles and the microbial metabolic byproducts such as short chain fatty acids (SCFAs) and retinoic acid (RA), that could ultimately impact the microbiome-liked immune pathways including regulatory T cells, autophagy, IL-10, IL-17, IL-22 and TGF-beta. In addition to bacteria, this project will determine changes and impacts from parasites, fungi and viruses? compositions, which were missed in previous TB studies. This study will address how drug related-dysbiosis would impact microbiome-derived metabolites that are important for immune cells responsiveness to TB. Understanding the dynamic of microbiome related-immune disorders during and after treatment will elucidate the contribution of microbiome in TB immune response in general with applications in designing future better vaccines and more effective treatments. The specific aims of the project are to: 1) Determine the longitudinal dynamics of the microbiome immune metabolic functions during and after tuberculosis therapy, and 2) Determine the evolution of microbiome linked inflammatory markers during and after tuberculosis therapy. This project may lead to new TB vaccine and treatment strategies.